RU2003119658A

RU2003119658A - TETRALON DERIVATIVES AS ANTI-TUMOR AGENTS

Info

Publication number: RU2003119658A
Application number: RU2003119658/04A
Authority: RU
Inventors: ГЕОРГЕС Гай; ГРОССМАНН Адельберт; ЗАТТЕЛЬКАУ Тим; Шефер Вольфганг; ТИБЕС Ульрих
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 2000-12-07
Filing date: 2001-12-06
Publication date: 2004-12-27

Claims

1. The compound of formula (I)

where R1 is selected from the series hydrogen, C ₁ -C ₄ alkyl, COOH, COO (C ₁ -C ₄ ) alkyl,

R2, R3, R4, R5 are independently selected from the series hydrogen, halogen, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxy, C ₁ -C ₄ alkoxy, aryloxy, arylalkyloxy, nitro, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) amino, piperidino, morpholino, pyrrolidino, C ₁ -C ₄ alkanoylamino, or aryl or heteroaryl, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, form a C ₁ -C ₃ alkylenedioxy ring, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, form a C ₃ -C ₅ alkylene chain,

Y is —CH ₂ —CH ₂ -,

X means an alkylene chain containing from 4 to 10 carbon atoms, which is saturated or unsaturated, may contain one or two double bonds, or one or two triple bonds, or one double and one triple bond, may be branched or unbranched or interrupted by a C ₃ ring -C ₇ cycloalkyl, its enantiomers, diastereomers and racemates, as well as its salts with pharmaceutically acceptable acids and bases.

2. The compound of formula I according to claim 1, in which R1 is hydrogen or C ₁ -C ₄ alkyl or COOR, where R is hydrogen or C ₁ -C ₄ alkyl.

3. The compound of formula I according to claim 1, in which R2, R3, R4 and R5 independently mean hydrogen or three of them mean hydrogen or R2 and R5 mean hydrogen.

4. The compound of formula I according to claim 1, where X is - (CH ₂ ) _n - or -CH = CH- (CH ₂ ) _n-2 -, where n is an integer from 3 to 7.

5. The compound of formula I according to claim 1, where X means - (CH ₂ ) _n-1 -CH (CH ₃ ) -, - (CH ₂ ) _n-1- CH (CH ₃ ) ₂ - or - (CH ₂ ) _n-1 -C (-CH ₂ -CH ₂ -) -, where n is an integer from 3 to 7.

6. The compound of formula I according to claim 1, selected from the group including

5- (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) pentanoic acid hydroxyamide,

5- (6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) pentanoic acid hydroxyamide,

6- (6-chloro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) hexanoic acid hydroxyamide,

6- (2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) hexanoic acid hydroxyamide,

6- (1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) hexanoic acid hydroxyamide,

5- (2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) pentanoic acid hydroxyamide,

6- (2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) hex-5-enoic acid hydroxyamide,

5- (5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) hexanoic acid hydroxyamide,

2- (5-hydroxycarbamoylpentyl) -5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid ethyl ester,

2- (7-hydroxycarbamoylheptyl) -5,7-dimethyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid ethyl ester,

6- (7-chloro-2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) hexanoic acid hydroxyamide.

7. A method of obtaining a compound of formula I

Where

R1 is selected from the range of hydrogen, C ₁ -C ₄ alkyl, COOH, COO (C ₁ -C ₄ ) alkyl, R2, R3, R4, R5 are independently selected from the range of hydrogen, halogen, C ₁ -C ₄ alkyl-, trifluoromethyl- , hydroxy, C ₁ -C ₄ alkoxy, aryloxy, arylalkyloxy, nitro, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) amino, piperidino, morpholino, pyrrolidino, C ₁ -C ₄ alkanoylamino, or aryl or heteroaryl, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, can mean a cycle C ₁ -C ₃ alkylenedioxy, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, can represent a C ₃ -C ₅ alkylene chain,

Y is —CH ₂ —CH ₂ -,

X means an alkylene chain containing from 4 to 10 carbon atoms, which is saturated or unsaturated, may contain one or two double bonds, or one or two triple bonds, or one double and one triple bond, may be branched or unbranched or interrupted by a C ₃ ring —C ₇ cycloalkyl, its enantiomers, diastereomers and racemates, as well as its salts with pharmaceutically acceptable acids or bases, by reacting a compound of formula III

where R1, R2, R3, R4, R5 and Y are as defined above, with a compound of formula IV

where A is a leaving group, PG is a protecting group, and X is as defined above.

8. A pharmaceutical composition containing the active ingredient in the form of a compound of formula I according to any one of claims 1 to 6, in a mixture with a pharmaceutically acceptable carrier, excipients or diluents.

9. The use of compounds according to claims 1-6 for the preparation of a medicament having inhibitory activity against histone deacetylase (HDAC)

10. The use of a compound according to claim 9 as an inducer of apoptosis or an inhibitor of cell proliferation.